Revolutionary advances in imaging drive discovery in the biomedical sciences. These advances in imaging depend on innovations in technology throughout the physical and biological sciences. In recent decades, a number of significant breakthroughs have underscored the importance of this interdependent relationship between technology and biomedical science. One important discovery that culminated in the 2008 Nobel Prize was the work of Tsien et al. that led to the structure, expression, and optimization of fluorescent proteins for biomedical imaging applications. There have been other key discoveries in the areas of imaging technology, contrast agents and clinical applications. For example, photoacoustic imaging combines the best attributes of optical imaging and ultrasound: high resolution and greater depth penetration. Multimodality imaging has evolved at a rapid pace, along with image fusion technology for co- registration of data sets from multimodal imaging studies at various biological scales, spatial and temporal resolutions. What are the challenges and frontier domains of imaging sciences in the 21st century? The following examples describe challenges that are interconnected with advances in basic and translational sciences. (1) With progress in cell therapy and tissue engineering, noninvasive imaging of stem cells will be needed to ascertain delivery to target sites. (2) More hybrid imaging systems will be developed, such as PET and optical or photoacoustic imaging. (3) Nanoparticles with multimodality imaging capabilities and drug payloads will be optimized and moved into clinical trials. These challenges must be met by interdisciplinary teams of engineers, physicists, computer scientists, mathematicians, chemists, biologists, and physicians working together at the interfaces between biology, technology, and medicine to develop new imaging technologies, modalities, and applications. Washington University therefore launched the Imaging Sciences Pathway (ISP), which has been supported by a T90-R90 Roadmap Initiative grant that ended 7/31/10. This proposal requests continued support under a broad-based T32 mechanism for the interdisciplinary training of predoctoral students in our Imaging Sciences Pathway.